17-3636564-C-T

Variant names:

• chr17-3636564-C-T
• rs530371788
• ENST00000381870.8:c.-374C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001031681.3(CTNS):​c.-374C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 262,694 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (3 hom.)
• Consequence: CTNS NM_001031681.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.0500
• Publications: 0 publications found

Genes affected

CTNS (HGNC:2518): (cystinosin, lysosomal cystine transporter) This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

CTNS Gene-Disease associations (from GenCC):

• cystinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
• nephropathic cystinosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• juvenile nephropathic cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• ocular cystinosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• nephropathic infantile cystinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00275 (419/152342) while in subpopulation NFE AF = 0.00475 (323/68010). AF 95% confidence interval is 0.00432. There are 2 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031681.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	NM_001031681.3		c.-374C>T		5_prime_UTR	Exon 1 of 13	NP_001026851.2	O60931-2
	CTNS	NM_004937.3	MANE Select	c.-497C>T		upstream_gene	N/A	NP_004928.2	O60931-1
	CTNS	NM_001374492.1		c.-497C>T		upstream_gene	N/A	NP_001361421.1	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000381870.8	TSL:1	c.-374C>T		5_prime_UTR	Exon 1 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.-369C>T		5_prime_UTR	Exon 1 of 12	ENSP00000500995.1	O60931-1
	CTNS	ENST00000901058.1		c.-374C>T		5_prime_UTR	Exon 1 of 12	ENSP00000571117.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152224 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00376 AC: 415 AN: 110352 Hom.: 3 Cov.: 0 AF XY: 0.00359 AC XY: 204 AN XY: 56866

African (AFR) AF: 0.00119 AC: 4 AN: 3362

American (AMR) AF: 0.00109 AC: 3 AN: 2764

Ashkenazi Jewish (ASJ) AF: 0.00258 AC: 11 AN: 4264

East Asian (EAS) AF: 0.00 AC: 0 AN: 8510

South Asian (SAS) AF: 0.000287 AC: 2 AN: 6964

European-Finnish (FIN) AF: 0.00424 AC: 32 AN: 7544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 564

European-Non Finnish (NFE) AF: 0.00497 AC: 344 AN: 69170

Other (OTH) AF: 0.00264 AC: 19 AN: 7210

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152342 Hom.: 2 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74500

African (AFR) AF: 0.00103 AC: 43 AN: 41600

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00255

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nephropathic cystinosis (1)
-	1	-	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.2
DANN	Benign	0.86
PhyloP100		-0.050
PromoterAI		-0.035	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs530371788; hg19: chr17-3539858;